Resilience of biochemical activity in protein domains in the face of structural divergence

Abstract

Recent studies point to the prevalence of the evolutionary phenomenon of drastic structural transformation of protein domains while continuing to preserve their basic biochemical function. These transformations span a wide spectrum, including simple domains incorporated into larger structural scaffolds, changes in the structural core, major active site shifts, topological rewiring and extensive structural transmogrifications. Proteins from biological conflict systems, such as toxin-antitoxin, restriction-modification, CRISPR/Cas, polymorphic toxin and secondary metabolism systems commonly display such transformations. These include endoDNases, metal-independent RNases, deaminases, ADP ribosyltransferases, immunity proteins, kinases and E1-like enzymes. In eukaryotes such transformations are seen in domains involved in chromatin-related peptide recognition and protein/DNA-modification. Intense selective pressures from 'arms-race'-like situations in conflict and macromolecular modification systems could favor drastic structural divergence while preserving function.

Figure 1. Spectrum of structural divergence which preserves biochemical function

The spectrum is broken up into distinct classes of structural divergence separated by dotted lines. Example structures are depicted as topology diagrams with arrows representing β-strands and coils representing α-helices. ‘B’ represents the ‘baseline’ class of structural divergence. Class 1: representatives of papain-like peptidases; Class 2: restriction endonuclease fold with modified part of the secondary structural elements colored in yellow; Class 3: BECR fold members with divergent active site residues highlighted in green; Class 4: transition between NFACT and Fpg-MutM-EndoVIII DNA glycosylase proteins are accompanied by linear arrays of secondary structural elements to show rewiring, each duplicated basic 4-stranded element is given a distinct color; Class 5: topological transmogrification observed in the obligate dimer-forming BcbF family of HAD domains, strands are labeled, and monomers are given distinct colors.

Figure 2. Structural diversity of HNH endonucleases

The α-helix and β-sheet of the HNH structural core are shown in red and aquamarine respectively. Metals, active site (blue) and zinc chelating (in green) residues are shown in the ball and stick mode. Other incorporated structural elements are in light blue. The duplicated three-stranded units of NucA are shown in light blue and light brown respectively.

Figure 3. Cartoon representations of various STY kinase domains illustrating the structural transformations in the superfamily

Helices are colored red, whereas strands are colored based on their structural unit. Strands of the top unit are colored yellow and those in the central sheet, magenta. The cyan and pink strands of the bottom unit show the equivalence of these strands between the structures.

Figure 4. Topological and spatial transmogrifications in SUKH, SuFu and Imm75 families

The shared structural elements of these families are equivalently colored in the topological and cartoon representations. The type of structural transition with respect to the SUKH domain is shown above the topology.

Figure 5. Biological context of proteins showing major structural variations

Key components of each biological system are illustrated with the proteins and domains showing major structural variations highlighted in light blue.